Potentially Causal Associations Between Extensive Gastric Atrophy and Esophageal Squamous Cell Carcinoma: A Nationwide Retrospective Cohort Study in Japan

ABSTRACT Objectives A potential association between esophageal squamous cell carcinoma (ESCC) and gastric atrophy (GA) has been reported. However, most published studies have used case–control designs, leading to selection bias. This study aimed to investigate the causal association between ESCC and GA using a nationwide cohort. Methods A retrospective cohort study was conducted on consecutive participants who underwent endoscopy at 17 health check‐up institutes in Japan between 2013 and 2017, with at least one follow‐up endoscopy by December 2022. GA was evaluated endoscopically and classified into atrophy‐free, closed‐type, and open‐type GA. The association between ESCC incidence and GA was estimated using the Kaplan–Meier method and Cox regression. Results Among 33,461 participants, 17,398 (52.0%), 8257 (24.7%), and 7804 (23.3%) were classified into atrophy‐free, closed‐type GA, and open‐type GA, respectively. Seventy‐seven ESCCs were identified during a median 6‐year follow‐up period. The incidence of ESCC was 24 cases (0.024%/year) in the atrophy‐free group, 15 cases (0.031%/year) in the closed‐type GA group, and 38 cases (0.089%/year) in the open‐type GA group, with a significantly higher incidence observed in the open‐type GA group ( p < 0.001). After adjusting for established risk factors (e.g., age, sex, drinking, and smoking), open‐type GA, but not closed‐type GA, was an independent risk factor for ESCC (adjusted hazard ratio: 2.72, 95% confidence interval: 1.58–4.69). Conclusions This Japanese nationwide cohort study provides new evidence suggesting a causal association between extensive GA and the subsequent development of ESCC.